IgG-Switched CLL Has a Distinct Immunogenetic Signature from the Common MD Variant : Ontogenetic Implications

• PURPOSE:IgG-switched chronic lymphocytic leukemia (G-CLL) is a rare variant of CLL, whose origin and ontogenetic relationship to the common IgM/IgD (MD-CLL) variant remains undefined. Here we sought for clues regarding the ontogeny of G-CLL versus MD-CLL by profiling the relevant IG gene repertoires.EXPERIMENTAL DESIGN:Using purpose-built bioinformatics methods, we performed detailed immunogenetic profiling of a multinational CLL cohort comprising 1256 cases, of which 1087 and 169 expressed IG mu/delta and gamma heavy chains, respectively.RESULTS:G-CLL has a highly skewed IG gene repertoire that is distinct from MD-CLL, especially in terms of: (i) overuse of the IGHV4-34 and IGHV4-39 genes; and, (ii) differential somatic hypermutation (SHM) load. Repertoire differences held also when comparing subgroups with similar SHM status and were mainly attributed to the exclusive representation in G-CLL of two major subsets with quasi-identical (stereotyped) B-cell receptors. These subsets, namely #4 (IGHV4-34/IGKV2-30) and #8 (IGHV4-39/IGKV1(D)-39), were found to display sharply contrasting SHM and clinical behavior.CONCLUSIONS:G-CLL exhibits an overall distinct immunogenetic signature from MD-CLL, prompting speculations about distinct ontogenetic derivation and/or immune triggering. The reasons underlying the differential regulation of SHM among G-CLL cases remain to be elucidated.

Publication and Content Type

ref (subject category)

art (subject category)